Antibiotic resistance and persistent infections refractory to per os or injected treatments are a major problem in bacteriological transmissions, resistance to eradication and ultimately pathogenesis. While the consequences of bacterial resistance and bacterial recalcitrance are the same, there are two different mechanisms that explain the two processes.                Antibiotic/Antimicrobial Resistance. In the case of antibiotic or antimicrobial resistance, biofilms provide the unique opportunity for bacterial to reside in close proximity with one another for long periods of time. This prolonged juxtaposition of bacterial allows gene transfer between and among bacteria, allowing the genes of resistance to be transferred to same or different strains of bacteria to neighboring cells that are not resistant. Consequently, a virulent cell can transfer its virulence genes to a non-virulent cell, making it resistant to antibiotics.        Antibiotic/Antimicrobial Recalcitrance. In the case of antibiotic or antimicrobial recalcitrance, there are two possible explanations, both of which involve the biofilm and both of which may be operative simultaneously. While gene transfer may occur, it is not a factor in recalcitrance.        
Biofilms are matrix-enclosed accumulations of microorganisms such as bacteria (with their associated bacteriophages), fungi, protozoa and viruses that may be associated with these elements. While biofilms are rarely composed of a single cell type, there are common circumstances where a particular cellular type predominates.
Biofilms are the most important primitive structure in nature. In a medical sense, biofilms are important because the majority of infections that occur in animals are biofilm-based. Infections from planktonic bacteria, for example, are only a minor cause of infectious disease.
In summary, the biofilm formation consists of planktonic cells adsorbing onto a surface, experience phenotypic transformations and form colonies. Once the colonizing cells become established, they secrete exopolysaccharides that serve as the backbone for the growing biofilm. While the core or backbone of the biofilm is derived from the cells themselves, other components e.g., lipids, proteins etc, over time, become part of the biofilm. Thus a biofilm is heterogeneous in its total composition, homogenous with respect to its backbone and heterogeneous with respect to its depth, creating diffusion gradients for materials and molecules that attempt to penetrate the biofilm structure.
The first of the explanatory mechanisms of resistance offered by biofilm is simply a physical phenomenon: the biofilm structures present a barrier to the penetration of antibiotics and antimicrobial agents and a protective shroud to physical agents such as ultraviolet radiation.
Another biofilm resistance mechanism is based on biochemical or metabolic principles. Just as the deep-seated bacterial are protected from chemical and physical agents by the “barrier” effect of the biofilm, the biofilm also acts as a barrier to nutrients that are necessary for normal metabolic activity. Further, the nutrient-limited bacteria are in a reduced state of metabolic activity, which make them less susceptible to chemical and physical agents because the maximal effects of these killing agents are achieved only when the bacteria are in a metabolically active state. In addition, biofilms are linked to other virulence factors of pathogens (like efflux pumps or alginate secretion).
In particular, biofilms constitute a growing problem for the treatment of respiratory diseases associated with infection like cystic fibrosis, diffuse panbronchiolitis, exacerbation of chronic obstructive pulmonary diseases, pneumonia, etc. . . . The treatments of those diseases with antibiotics become consequently more and more difficult due to the resistance offered by said biofilm.
Biofilms are associated with various bacteria, fungi and viruses among which Pseudomonas aeruginosa and Staphylococcus aureus cause the most dramatical consequences in the above cited respiratory diseases.
Whichever the mechanistic explanations for either resistance or recalcitrance, the removal or disruption of the biofilm is a mandatory requirement for the successful treatment of the infection.
Aminoglycoside antibiotics are very active antimicrobial agents but their use has been limited because of their high frequence of serious and irreversible adverse events associated with their use. The most common and important toxicity are nephrotoxicity and ototoxicity. Aminoglycosides are usually administered by intra-venous injection because they are very poorly absorbed by the oral route. Nevertheless, a nebulized formulation of Tobramycin (TORI®) to treat lung infections due to P. aeruginosa in Cystic Fibrosis patients is available.
TOBI® presents the advantage to allow to treat lung infections locally with a lower systemic exposure than the intravenous formulation and is thus responsible of less side-effects. However, due to low respiratory fraction compositions administered through nebulisation (5 to 8% of the nominal dose), the nominal dose to administer (300 mg of Tobramycin b.i.d.) is still too high and can be responsible of a significant frequency and/or severity of side-effects.
Although, aminoglycoside antibiotics are very effective against several planktonic bacteria, they are much less effective if not ineffective against the same bacterial which have formed a biofilm. This phenomenon of resistance of biofilms is also true for other antibiotics and represents a major public health concern. In some specific lung diseases like cystic fibrosis and diffuse panbronchiolitis, it is of major importance to dispose of compositions which are able to destroy, disorganize, inhibit the biofilm and/or able to prevent its formation.
Oral dosage formulations of macrolides antibiotics are widely used to treat, among others, respiratory infections like acute exacerbations of chronic bronchitis, sinusitis, rhinopharyngitis, . . .
While macrolides antibiotics are mostly available as oral dosage forms containing several hundreds of milligrams of the antibiotic, no inhaled form has been available up to now, because amounts of hundreds of mg are impossible to administer ambulatorily by inhalation through systems like dry powder inhalers or metered dose inhalers.
In summary, oral and intravenous antibiotic compositions used to treat bacterial infections are efficient not and safe against bacterial biofilms responsible for lung infections or surinfections.
Consequently, there is an urgent need for efficient and safe antibiotic compositions, administered directly in the lung and able to treat lung infections due to biofilms. The present invention discloses a dry powder composition for inhalation allowing to obtain a) a high pulmonary amount of aminoglycoside antibiotic and b) high dose of a biofilm modifyer which is selected from the group of macrolides and derivatives, which is efficacious against said biofilm when administered directly into the lungs.